Linagliptin has a IUPAC name of 8-[(3R)-3-aminopiperidin-1-yl]-7-(but-2-yn-1-yl)-3,7-dihydro-3-methyl-1-[(4-methylquinazolin-2-yl)methyl]-1H-purine-2,6-dione, and a molecular structure formula as follows:

Linagliptin is an oral hypoglycemic drug developed by Boehringer Ingelheim Pharmaceuticals Inc., Germany, which is approved by the US FDA on May 2, 2011 and marketed under the trade name Tradjenta. Linagliptin is used to control the glycemic level of patients primarily by inhibiting DPP-IV, and further used to control the glycemic level of type 2 diabetic patients in conjunction with diet and exercise.
WO 2004/018468 discloses synthetic examples of 8-[3-aminopiperidin-1-yl]xanthines, the tautomers, non-enantiomers, racemates and salts thereof.

WO 2006/048427 discloses an improved process for preparing chiral 8-[3-aminopiperidin-1-yl]xanthines, their enantiomers and their physiologically tolerable salts.

In both of the above two processes, 8-[3-aminopiperidin-1-yl]xanthines are prepared by reacting the xanthine precursor VII successively with 2-chloromethyl-4-methylquinazoline (III) and 3-aminopiperidine derivative via N-alkylation reaction to give the corresponding N-protected Linagliptin derivative (V), which is finally deprotected to prepare Linagliptin (I).
In the above preparation processes, the solvent used is N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), or the like, which are water-soluble, the intermediate in each step requires separation and purification, in which water is added directly for crystallization, and the solvent is hardly to be recycled, causing a great pollution by liquid waste. In addition, the separation of the intermediates is complicated and has along production cycle and a high energy consumption, which is difficult to satisfy the requirement of “green chemistry” in industrial production. Furthermore, the final product obtained by the above synthetic process needs to be isolated and purified by column chromatography, which is difficult to meet the demand for industrial mass production.
Therefore, there is still a need for a process for preparing linagliptin derivatives with high yield, simple operation, which is environmentally friendly and suitable for industrial mass production, so that it is possible to prepare the linagliptin with excellent chemical and optical purity in industrial mass production.